The phenomenon of tumor promotion in two-stage carcinogenesis was systematically explored in various rodent species in conjuction with transplacental carcinogenesis. Tumor-promoting activities of various pharmacologically defined classes of compounds (e.g., barbiturates, benzodiazepine tranquilizers) and environmental pollutants (e.g., the plasticizer, di-2-ethylhexylphthalate, and its major metabolites) are determined by sequential administration to animals of a transient, low level exposure to a genotoxic carcinogen followed by the test agent under study. The appearance of preneoplastic and neoplastic lesions is quantitated in target animal tissues. Organ specificities and interspecies correlations in tumor promotion are investigated for clues to the mechanism(s) of action of tumor promoters. Barbital has been found to promote carcinogenesis in the rat renal cortical epithelium, as well as in the liver and thyroid follicular parenchyma. Long-acting anticonvulsant/sedative activity correlates with tumor promotion by barbiturates, and organ specificity varies with the pattern of substitution at C-5. Tumor-initiation capabilities of transplacentally active agents in various fetal tissues are determined following postnatal exposure of prenatally-treated offspring to various topical and systemic promoters. Thyroid follicular neoplasms and preneoplastic hepatocellular foci appeared in rats exposed prenatally to nitrosomethylurea and given phenobarbital postnatally, demonstrating the persistence in these "non-target" tissues of latent neoplastic cells resulting from transplacental exposure to the carcinogen. Premalignant JB-6 mouse epidermal cells are used to investigate the mechanisms of tumor promotion by various drugs and environmental pollutants.